Epigenetic drug screening identifies enzyme inhibitors A-196 and TMP-269 as novel regulators of sprouting angiogenesis

Journal article

Epigenetic therapy has gained interest in treating cardiovascular diseases, but preclinical studies often encounter challenges with cell-type-specific effects or batch-to-batch variation, which have limited identification of novel drug candidates targeting angiogenesis. To address these limitations and improve the reproducibility of epigenetic drug screening, we redesigned a 3D in vitro fibrin bead assay to utilize immortalized human aortic endothelial cells (TeloHAECs) and screened a focused compound library with 105 agents. Compared to the established model using primary human umbilical vein endothelial cells, TeloHAECs needed a higher-density fibrin gel for optimal sprouting, successfully forming sprouts under both normoxic and hypoxic cell culture conditions. We identified two epigenetic enzyme inhibitors as novel regulators of sprouting angiogenesis: A196, a selective SUV4-20H1/H2 inhibitor, demonstrated pro-angiogenic effects through increased H4K20me1 levels and upregulation of cell cycle associated genes, including MCM2 and CDK4. In contrast TMP-269, a selective class IIa HDAC inhibitor, exhibited anti-angiogenic effects by downregulating angiogenesis-related proteins and upregulating pro-inflammatory signaling. These findings highlight the suitability of the modified TeloHAEC fibrin bead assay for drug screening purposes and reveal both pro-angiogenic and anti-angiogenic drug candidates with therapeutic potential.

Authors: Beter, M; Pulkkinen, HH; Örd, T; Sormunen, A; Kilpeläinen, L

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Scientific Reports
• Volume: 15
• Issue: 1
• Article number: 1628
• Publication date: 2025-01-10
• Acceptance date: 2024-12-24
• DOI: 10.1038/s41598-024-84603-w
• EISSN: 2045-2322
• Language: English
• Keywords: TeloHAEC fibrin bead assay; Angiogenesis; TMP-269; A-196; Epigenetic therapy; Epigenetic screening